Turmeric has been used since ancient times in India and China as a dietary pigment and essential spice. It is also used in traditional/folk medicine as an antiseptic and anti-inflammatory agent and in wound healing. Curcumin has been identified as the active ingredient in turmeric. It is a yellow colored polyphenolic natural compound isolated from the rhizome of the herb Curcuma longa Linn which exhibits various biological activities including anti-inflammatory, antioxidant, antimicrobial, antiviral, chemopreventive, antiangiogenic, and anticancer activities. Curcumin has also shown hepato-protective and nephro-protective, thrombosis supressing, myocardial infarction protective, hypoglycemic, and antirheumatic activities.
Curcumin exhibits this wide range of biological activities due to its unique ability to interact with various biomolecules and biochemical pathways, which include cell proliferation pathways, caspase activation pathways, tumor suppressor pathways, transcriptional factors, cell survival pathways, mitochondrial pathways, protein kinase pathways, and death receptor pathways. The multi-targeting ability of curcumin has made it a focus for cancer chemoprevention and pharmacotherapy.
Toxicological studies conducted in animal models or in humans have shown that curcumin is safe even at a dose level of 12 g/d. The pharmacological safety and efficacy of curcumin makes it a potential compound for treatment and prevention of a wide variety of diseases. However, the poor solubility, poor bioavailability, and poor absorption as well as rapid metabolism are major problems associated with curcumin. Consequently, curcumin itself is not a good candidate for further clinical development. Much effort has been devoted to developing new curcumin analogues in order to solve the pharmacokinetic problems and at the same time to maintain high potency and low toxicity. Efforts have also been made to enhance its selectivity and potency for addressing the pathological diversity of human cancer.
In order to address these issues, numerous approaches have been explored to synthesize curcumin analogues and derivatives. The pharmacological studies conducted on curcumin indicate that the β-diketone functionality of curcumin is a substrate for liver aldoketo reductases and this may be a metabolism of curcumin in vivo. In order to improve the in vivo metabolic stability of curcumin (e.g., C7 curcuminoids), several curcumin analogues with a single carbonyl moiety (e.g., C5 curcuminoids) have been prepared and some of these compounds have exhibited anticancer activity.
The degree of in vivo degradation and pharmacokinetic studies suggest that these compounds are more stable and exhibit increased activity compared to curcumin. Structure activity relationship studies conducted on these compounds revealed that the heteroaromatic core in these compounds correlated with high anti-proliferative and anti-inflammatory activities.
There exists a need for the synthesis of new C5 curcumin analogues, which are stable, bioavailable, and exhibit the desired biological activity.
Accordingly, it is an object of the invention to provide new stable, bioavailable C5 curcumin analogues and exhibit the desired biological activity, and methods of making and using thereof.